2 - trichloromethyl - 4 - morpholino-6-(succinyloxy alkyl)amino - s - triazines and lower alkyl esters thereof



United States Patent 3,536,709 2 TRICHLOROMETHYL 4 MORPHOLINO-6-(SUCC1NYLOXY ALKYL)AMINO s TRI- AZINES AND LOWER ALKYL ESTERS THEREOFWerner Heimberger, Hanan am Main, Germany, assignor to Dentsche GoldundSilber-Scheideanstalt vorrnals Roessler, Frankfurt am Main, Germany NoDrawing. Filed May 22, 1967, Ser. No. 640,349 Claims priority,applicatirgll) 1Gelrmany, May 21, 1966,

Int. Cl. c6711 87/42 US. Cl. 260---247.2 4 Claims ABSTRACT OF THEDISCLOSURE Dicarboxylic acid derivatives of s-triazine of the formula NN-CO-(OHzh-COOH in which n is an integer of from 1 to 6 and Alk is astraight or branch chained alkylene of 1 to 4 carbon atoms and theirpharmacologically acceptable salts, especially their alkali metal andalkaline earth metal salts, their addition salts with pharmacologicallyacceptable bases, as well as their alkyl esters wherein the alkyl is of1 to 4 carbon atoms.

The compounds are useful as analgesics and as antiinfiammatory agents.

Field of the invention The invention relates to novel dicarboxylic acidderivatives of 2,4,6 substituted s-triazines [which are useful asantiinflammatory agents and particularly as analgesics.

Summary of the invention The invention concerns novel dicarboxylic acidderivatives of s-triazine of the formula in which R and R may be thesame or diiferent and signifying alkoxyor alkylthio of 1 to 4 carbonatoms, a straight or branched monoalkylamino or monoalkanolamino groupof 1 to 4 carbon atoms, CCl CHCl 3,536,709 Patented Oct. 27, 1970 'Ol,morpholino, piperazino or N-alkyl pipera/zino in which the alkyl is of 1to 4 carbon atoms and R signifies as well as their alkyl esters whereinthe alkyl is of 1 to 4 carbon atoms.

The compounds are useful as analgesics and as antiinflammatory agents.

Detailed description of the invention including the preferredembodiments The novel compounds according to the invention which are asdescribed under the summary of the invention can be produced by reactinga compound of the formula wherein and Alk, R and R have the samesignificance as above in an organic solvent, preferably under exclusionof water with about equimolecular quantities of the correspondingdicarboxylic anhydride or dicarboxylic acid ester halide (a) by heating,if desired under reflux and if desired in the presence of a base or (b)in the presence of equimolecular quantities of a tertiary organicnitrogen base, if desired at an elevated temperature to produce thecorresponding onium salt and recovering the desired product in a knownmanner.

It is advantageous to employ ethyl acetate or methylene chloride as theorganic solvent, however, solvents such as acetone or halogenatedhydrocarbons may be employed.

Aromatic, aliphatic or mixed aromatic-aliphatic tertiary organicnitrogen bases, such as, for instance, pyridine,

collidine, trialkyl amines, preferably, triethyl amine, may

be employed as the tertiary organic nitrogen bases.

When the process is carried out as under (a) the reaction mixture, forexample, may be heated under reflux, if desired, and after cooling downthe solution is shaken out with weakly alkaline water, slightlyacidifying the aqueous phase whereupon the triazine compound precipitates out.

When the process is carried out under (b) it is expedient to employtemperatures between room temperature and about 60 C. If the onium saltprecipitates out in crystalline form, it is expedient to isolate it andWash it. Thereafter it can be dissolved in water and be acidified withan acid to precipitate out the triazine compound. If the onium saltconcerned does not precipitate out, the reaction solution can be shakenout with water and the triazine recovered from the aqueous solution byacidification.

The starting piperazino, morpholino or alkanol amino substitutedtriazines can be produced by the methods analogous to those disclosed inUS. application Ser. No. 623,548, filed Mar. 16, 1967, by reactingtrichloromethyl substituted triazines with alkanol amines, morpholine orpiperazine.

As already indicated, the novel compounds according to the invention areuseful as antiinfiammatory antiphlogistic agents and particularly asanalgesics.

The compounds, for example, upon oral administration to mice in doses of300 to 400 mg./kg. have a strong analgesic action as determined by themouse tail test according to Hatfner and their acute toxicity (LDbetween about 900 to 1700 mg./ kg. The therapeutic index thereof isbetter than, for instance, that of phenacetin.

The application of the novel compounds may be enteral, for instance, inthe form of pills, capsules tablets, dragees, suppositories, oily oraqueous solutions or suspensions, or parenteral as injectable aqueous oroily solutions or suspensions.

The single dosage for relief of pain, depending upon the form ofapplication, may be between 1 and 500 mg. and may be administered one ormore times a day.

The following examples will serve to illustrate the novel compoundsaccording to the invention with reference to a number of representativeembodiments.

In the formulae given in the examples represents the s-triazine nucleusEXAMPLE 1 37.5 g. (0.1 mol) of 2,4-bis-trichloromethyl-6-ethanolamino-s-triazine were stirred with g. 0.1 mol) of succinic acidanhydride in 60 ml. of ethyl acetate at 20 C. and 10.1 g. (0.1 mol) oftriethyl amine slowly added thereto while cooling, whereupon solutionoccurred. After a short period of time the triethyl ammonium salt beganto crystallize out. It Was filtered off and washed. Its melting pointwas 99103 C. The salt was dissolved in water and HCl added to provide apH of 6 whereupon the 2,4-bis-trichloromethyl 6(Z-succinyloxyethyl)-aminos-t'riazine:

precipitated out as free acid. Yield: 41 g. or 86% of theory. Meltingpoint 1121 18 C.

EXAMPLE 2 34.2 g. (0.1 mol) of 2-trichlorornethyl-4-morpholino-6-ethanolamino-s-triazine were heated to 50 C. in 150 ml. of dried ethylacetate together with 10.5 g. (0.105 mol) of succinic acid anhydride and10.6 g. (0.105 mol) of triethylamine, whereupon solution occurred. After30 minutes the reaction mixture was permitted to cool down and then shken out. wi h Wat r whereupon the triethyl- 4 amine salt Went over intothe aqeuous phase. Upon adjustment of the pH of the aqueous solution to4 the 2-trichloromethyl-4-morpholino 6 (2succinyl-oxyethyl)-aminos-triazine l HGHz-Gfir-Q-O O(CHz)2-COOH isobtained in free acid form. After washing and drying the yield was 38 g.or 86% of theory (melting point 176- 178 C.).

EXAMPLE 3 35.7 g. (0.1 mol) of 2-trichloromethyl-4-morpholino-6-(Z-hydroxypropyl)-amino-s-triazine were heated under reflux for onehour in 150 ml. of ethyl acetate while stirring together with 10.5 g.(0.105 mol) of succinic acid anhydride and 10.6 g. 0.105 mol) oftriethylamine. Solution occurred and after the reaction mixture hadcooled down the salt was extracted with water and the free acidprecipitated from the extract with the aid of HCl. 34 g. of 2trichloromethyl-4-morpholino-6-(2-succinyl-oxypropyl) -amino-s-trazinewere obtained. The melting point thereof was 160-161 C. and the yieldwas 74.5% of theory.

EXAMPLE 4 28.6 g. (0.08 mol) of 2-trichloromethyl-4-N'-methylpiperazino-6-ethanolamino-s-triazine were heated under reflux for 1 hourin ml. of ethyl acetate together with 8.4 g. (0.084 mol) of succinicacid anhydride. Solution occurred and after cooling the reaction mixturewas shaken out with aqueous sodium bicarbonate. The resulting aqueousphase was acidified to a pH of 6 by addition of HCl to precipitate theacid 2-trichloromethyl-4-N'-methylpiperazino-6- (2-succinyloxyethylamino-s-triazine NCH3 After filtering and washing with water the yield was 28g. or 76% of theory. Its melting point was 156-161 C.

EXAMPLE 5 oho- -N N-OH3 was obtained from the salt by treatment withHCl. The free acid had a melting point of 112118 C.

EXAMPLE 6 26.8 g. of 2-ethylamino-4-morpholino-6-ethanolaminos-triazine(0.1 mol) were stirred together with 10 g. of succinic acid anhydridechloride at room temperature whereupon the temperature rose to 38 C. andsolution occurred. After standing overnight the methylene chloridesolution was extracted with water. The resulting triethylamine saltsolution was adjusted to a pH of 6 by addition of HCl whereupon the2-ethylamino-4-morpholino-6-(2- succiny1oxyethyl)-amino-s-triazineNHOHz-CH:OC O'(CH2)z-COOH HIII N precipitated out. Yield: 29 g. (79% oftheory). Melting point: 196199 C.

EXAMPLE 7 g. (90% of theory). Melting point:

occurred. Yield: 39 212-217 C.

EXAMPLE 8 precipitated out. Yield: 42 g. or 92% of theory. Meltingpoint: 200-202 C.

EXAMPLE 9 26.5 g. of 2-ethylamino-4-i-propylamino-6-piperazinos-tn'azinewere stirred with 8 g. (0.1 mol) of pyridine in 150 ml. of methylenechloride. Then 10 g. of succinic acid anhydride were added thereto atroom temperature over a period of /2 hour, whereupon the reactionmixture heated to 35 C. and solution occurred. The pyridium salt whichwas formed was extracted from the methylene chloride solution with waterand HCl added to the extract to adjust its pH to 6, whereupon2-ethylamino-4-i-propylamino-6-N-succinylpiperazino-s-triazine H C zHNprecipitated out. Yield: 32 g. or 8 8% of theory. Melting point:1'83-l85 C.

EXAMPLE 10 26 g. of 2-chloro-4-morpholino-6-ethanolamino-s-triazine werestirred with 8 g. (0.1 mol) of pyridine in 200 ml. of ethylene chlorideand 10 g. of succinic acid anhydride added. The mixture was allowed tostand overnight at room temperature. The pyridine salt produced wasextracted with water and converted to the free acid with 6 H01. Yield:24 g. or 67% of theory of2-chloro-4-morpholine-6-succinyloxyethylamino-s-triazineNHCHr-CHz-O-CO-(CHzh-COOH Melting point: 173-178 C.

EXAMPLE 11 34.2 g. of2-trichloromethyl-4-morpholino-6-ethylenediamine-s-triazine were stirredwith 10.1 g. of triethylamine in 200 m1. of methylene chloride at roomtemperature. 10 g. of succinic acid anhydride were added thereto over aperiod of /2 hour while cooling to 25 C. After 2 hours the methylenechloride solution was extracted with water and the extract adjusted to apH of 4 with HCl. 2- trichloromethyl 4 morpholino-6-N'-succinylethylenediamine-s-triazine precipitated out. Yield: 38 g. or 86% of theory.Melting point: 187l90 C.

EXAMPLE 12 35.7 g. of 2-trichloromethyl-4-morpholino-6-(2-hydroxypropyl)-amino-s-triazine were suspended in 200 ml. of ethyl acetate andrefluxed for 1 hour with 12 g. of glutaric acid anhydride and 10.1 g. oftriethylamine, whereupon solution occurred. The resulting salt wasextracted with water and the aqueous extract adjusted to a pH of 6 withHCl, whereupon a syrupy product separated out which was then taken up in150 ml. of methylene chloride. The resulting solution was boiled downand the residue stirred with 1:1 ether-hexane, whereupon crystallizationoccurred. Yield: 33 g. or 70% of theory of 2-trichloromethyl-4-morpholino-6-(2 oxyglutarylpropyl)- amino-s-triazineMelting point: 119-122 C.

EXAMPLE 13 Melting point: 7882 C.

I claim: 1. An s-triazine of the formula wherein R is C01 and R ismorpholino and R is -NH-Alk-O-CO--(CH C0OH wherein Alk is straight orbranched alkylene of 1 to 4 No references cited.

carbon atoms, a pharmacologically acceptable salt or a 1 to 4 alkylester thereof. ALEX MAZEL, Primary Examiner 2. 2 trichloromethyl 4morpholino 6 (2-suc- L TOVAR Assistant Examinercinyloxyethyl)amino-s-triazine. 5

3. 2 trichloromethyl 4 m0rpho1in0-6-(2-succinyls 1 oxypropyl)-arnino-s-triazine.

4. 2 trichloromethyl 4 morpholino 6-(rneth0xy- 260 249'9; 424-4248 249succinyloxyethyl)-arnino-s-triazine.

